PEARLDIFER - A Phase II study of pemigatinib after curative local therapy in locally advanced intrahepatic cholangiocarcinoma (iCCA) harboring FGFR2 fusions/rearrangements

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Frankfurter Institut Fuer Klinische Krebsforschung IKF GmbH

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

11 Nov 2022 → 27 Mar 2025

Decision date (initial)

2024-08-19

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Incyte Biosciences

External identifiers

EU CT number

2024-512018-16-00

EudraCT number

2021-006232-50

ClinicalTrials.gov

NCT05565794

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Therapy, Efficacy

To assess the efficacy of pemigatinib administered after curative local therapy in treatment-naïve patients with resectable intrahepatic biliary tract cancer.

Secondary objectives 1

1. To assess the efficacy by overall survival (OS) and recurrence free survival (RFS); to assess safety of the treatment (AEs, impact on liver function, use of subsequent therapies); to assess quality of life (QoL).

Conditions and MedDRA coding

locally advanced intrahepatic cholangiocarcinoma (iCCA) with FGFR2 fusions/rearrangements

Regulatory references

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 14

1. Signed informed consent form (ICF).
2. For patients with active hepatitis B virus (HBV): HBV DNA ≤ 500 IU/mL obtained within 28 days prior to initiation of study treatment, AND Anti-HBV treatment (per local standard of care e.g. entecavir) prior to study entry and willingness to continue treatment for the length of the study.
3. For patients with active hepatitis C virus (HCV): Patients positive for HCV antibody are eligible, also if polymerase chain reaction testing is positive for HCV RNA; however, anti-viral therapy against HCV is only allowed prior to trial but not during the trial.
4. Patients infected with human immunodeficiency virus (HIV) are eligible if they meet all the following criteria: (a) CD4 count is ≥350 cells/uL, viral load is undetectable, and not taking prohibited cytochrome (CYP)-interacting medications; (b) Probable long-term survival with HIV if cancer were not present; (c) Stable on a highly active antiretroviral therapy (HAART) regimen for ≥4 weeks and willing to adhere to their HAART regimen with minimal overlapping toxicity and drug-drug interactions with the experimental agents in this study; (d) HIV is not multi-drug resistant; (e) Taking medication and/or receiving antiretroviral therapy that does not interact or have overlapping toxicities with the study medication
5. Patients*, age ≥ 18 years at the time of signing the informed consent form. (*There are no data that indicate special gender distribution. Therefore, patients will be enrolled in the study gender-independently.)
6. Histologically proven and curatively treatable localized intrahepatic biliary tract cancer (iCCA only), without signs of metastatic disease, and proven FGRF2-fusions/rearrangements, identified by routine FISH or by NGS testing. NOTE: Only CE-IVD marked NGS-tests are applicable which cover FGFR2 fusions and rearrangements.
7. Patients previously received local therapy for iCCA in form of curative surgery/ SBRT/ ablation or other local curative therapy up to 12 weeks prior to enrollment (initiation of conventional adjuvant systemic therapy without signs of PD might be permitted for bridging the time gap to achieve FGFR2-results - only after consultation with the LKP).
8. Female patients who are considered as woman of childbearing potential (WOCBP) as well as male patients who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year during the treatment as well as up to 1 week after the last dose of pemigatinib. Female patients who are not of childbearing potential (i.e., who are postmenopausal or surgically sterile, see section 13.5) as well as azoospermic male patients do not require contraception. Female patients considered as WOCBP must have a negative pregnancy test within the last 7 days prior to the start of study therapy.
9. ECOG performance status 0-1.
10. Appropriate hematological, hepatic and renal function: (a) Absolute number of neutrophils ≥ 1.5 x 10^9/L; (b) Platelets ≥ 100 x 10^9/L; (c) Hemoglobin ≥ 9 g/dL (5.58 mmol/L); (d) Total bilirubin ≤ 1.5 times the upper limit of normal (ULN); (e) AST (SGOT) and ALT (SGPT) ≤ 2.5 x ULN; AP ≤ 5 x ULN.
11. Serum creatinine ≤ 1.5 x ULN or creatinine clearance (measured by 24h urine) ≥ 40 mL/min (i.e., if the serum creatinine level is > 1.5 x ULN, then a 24-h urine test must be performed to check the creatinine clearance to be determined).
12. Adequate coagulability, as determined by the International Normalized Ratio (INR) ≤ 1.5 and partial thromboplastin time (PTT) ≤ 5 s above the ULN (unless anti-coagulation therapy has been given). Patients receiving warfarin / Phenoprocoumon must be switched to low molecular weight heparin before starting any study-specific procedures.
13. Patients infected with human immunodeficiency virus (HIV) are eligible if they meet all the following criteria: (a) CD4 count is ≥350 cells/uL, viral load is undetectable, and not taking prohibited cytochrome (CYP)-interacting medications; (b) Probable long-term survival with HIV if cancer were not present; (c) Stable on a highly active antiretroviral therapy (HAART) regimen for ≥4 weeks and willing to adhere to their HAART regimen with minimal overlapping toxicity and drug-drug interactions with the experimental agents in this study; (d) HIV is not multi-drug resistant; (e) Taking medication and/or receiving antiretroviral therapy that does not interact or have overlapping toxicities with the study medication
14. Subject is willing and able to comply with the protocol (including contraceptive measures) for the duration of the study including undergoing treatment, and scheduled visits and examinations including follow up.

Exclusion criteria 22

1. Presence of tumors other than biliary tract cancer or a secondary tumor other than squamous or basal cell carcinomas of the skin or in situ carcinomas of the cervix which have been effectively treated. The Sponsor decides to include patients who have received curative treatment and have been disease-free for at least 3 years.
2. Metastatic biliary tract cancer (intrahepatic, hilar, or distal CCA as well as gallbladder carcinoma) disease.
3. Pretreatment with any systemic anti-cancer therapy. NOTE: initiation of conventional adjuvant systemic therapy without signs of PD for bridging the time gap to achieve FGFR2-results might be permitted - only after consultation with the LKP.
4. Simultaneous, ongoing systemic immunotherapy, chemotherapy, or hormone therapy not described in the study protocol.
5. Simultaneous treatment with a different anti-cancer therapy other than that provided in the study (excluding palliative radiotherapy only for symptom control).
6. Previous therapy with an FGFR-inhibitor.
7. Stage B cirrhosis according to Child-Pugh criteria (or worse) or cirrhosis (of any grade) with a history of hepatic encephalopathy or clinically significant ascites resulting from cirrhosis. Clinically significant ascites is defined as ascites resulting from cirrhosis requiring diuretics or paracentesis.
8. Known allergic / hypersensitive reactions to at least one of the treatment components.
9. Other serious illnesses or medical ailments within the last 12 months prior to the start of the study.
10. Current evidence of clinically significant corneal (including but not limited to bullous/band keratopathy, corneal abrasion, inflammation/ulceration, and keratoconjunctivitis) or retinal disorder (including but not limited to central serous retinopathy, macular/retinal degeneration, diabetic retinopathy, retinal detachment) as confirmed by ophthalmologic examination.
11. History of calcium and phosphate hemostasis disorder or systemic mineral imbalance with ectopic calcification of soft tissues (exception: commonly observed calcifications in soft tissues, such as the skin, kidney, tendons or vessels due to injury, disease, and aging, in the absence of systemic mineral imbalance).
12. History of hypovitaminosis D requiring supraphysiologic doses (eg, 50,000 UI/weekly) to replenish the deficiency. NOTE: Participants receiving vitamin D supplements are eligible.
13. Use of any potent CYP3A4 inhibitors or inducers or moderate CYP3A4 inducers within 14 days or 5 half-lives (whichever is longer) before the first dose of study treatment. NOTE: Moderate CYP3A4 inhibitors are not prohibited (refer to section 24.3 Appendix 3 for a list of CYP3A4 inhibitors and inducers).
14. Presence of an active, uncontrollable infection.
15. Has active infection with SARS-CoV-2 (positive antigen test in routine testing at site).
16. Chronic inflammatory bowel disease.
17. Active disseminated intravascular coagulation.
18. Any other serious concomitant or medical condition that, in the opinion of the investigator, presents a high risk of complications to the patient or reduces the likelihood of clinical effect.
19. On-treatment participation in another interventional clinical study in the period 30 days prior to inclusion and during the study.
20. Patient pregnant or breast feeding, or planning to become pregnant
21. Patient in a closed institution according to an authority or court decision.
22. Subjects that are depending on the Sponsor/CRO or investigational site as well as on the investigator.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Recurrence free survival rate at 12 months (RFS@12)

Secondary endpoints 4

1. Incidence, treatment relationship, seriousness, and severity of all AEs, SAEs according to CTCAE V5.0
2. Overall survival (OS)
3. Recurrence free survival (RFS)
4. Effect of therapy on global health status/quality of life and on other symptoms and scales of the EORTC-QLQ-C30, EORTC-QLQ-BIL21 and EQ-5D-5L after 6 and 12 months (proportion of patients with a better, stable, or worse score)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Frankfurter Institut Fuer Klinische Krebsforschung IKF GmbH

Sponsor organisation

Frankfurter Institut Fuer Klinische Krebsforschung IKF GmbH

Address

Steinbacher Hohl 2-26, Praunheim Praunheim

City

Frankfurt Am Main

Postcode

60488

Country

Germany

Scientific contact point

Organisation

Frankfurter Institut Fuer Klinische Krebsforschung IKF GmbH

Contact name

Clinical Trial Project Manager

Public contact point

Organisation

Frankfurter Institut Fuer Klinische Krebsforschung IKF GmbH

Contact name

Clinical Trial Project Manager

Locations

1 EU/EEA country · 11 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 12 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications